The broad goal of the Therapeutics Program, to discover and develop mechanism-based anticancer therapies, is being approached by (a) identifying new sites for therapeutic intervention focusing on regulation of cell cycle and apoptosis and on signal transduction, (b) investigating the mode of action of existing anticancer drugs with a view to improve their clinical utility and/or to identify new target sites, (c) delineating the basis for drug resistance to clinically useful drugs and devising circumvention strategies, (d) facilitating development of new anticancer therapies through phase I / II clinical trials, and (e) clinically validating the mode of new drug action and evaluating novel markers as response or prognostic indicators. The Therapeutics Program is comprised of 32 members arrayed into three interactive research themes involving Molecular Target Discovery, Drug Action and Resistance, and Therapeutic Development. Specific research activities within these themes include apoptosis, taxane analogs, signal transduction, vitamin D-based therapeutics, drug resistance and rational drug combinations. The Program is co-led by Carl W. Porter, PhD and Donald Trump, MD. Dr. Porter is a research scientist with long-standing interest in novel drug discovery and strong familiarity with all research and clinical components of the Program. Dr. Trump is a clinician scientist with extensive experience in clinical drug development and urologic cancers. The Therapeutics Program's peer-reviewed, cancer-related funding is $4.2 million (direct) in 2002; total extramural research is approximately $8M (direct). Of the 199 cancer-related publications since 1999, 32% are CCSG interactive. Recent preclinical findings have been translated into 13 ongoing clinical trials. During the past three years, the Program has recruited three senior members, Michael Brattain, PhD (Chair, Department of Pharmacology & Therapeutics), Donald Trump, MD (Senior Vice President for Clinical Research and Chair of Medicine) and Candace Johnson, PhD (Senior Vice President for Translational Research) and eight additional members from outside institutions. Future recruitment will focus on the pharmacological application of gene profiling, pharmacogenetics, molecularly targeted drug combinations and clinical pharmacology.